The soluble alpha-secretase product of the beta-amyloid precursor protein (sAPPalpha) is potently neuroprotective against calcium- mediated cell death caused by (1) excitotoxicity of the neurotransmitter glutamate, (2) oxygen and glucose deprivation encountered by neurons during and after stroke, and (3) neuro-degenerative conditions such as amyelotrophic lateral sclerosis and Alzheimer's disease. This research proposal seeks to identify genes in neurons that are regulated by sAPPalpha and its second messenger cGMP. sAPPalpha-regulated genes will be revealed by a combination of cDNA array and differential display RT-PCR approaches. The identified genes are expected to be involved in sAPPalpha-mediated neuroprotection. Plans to identify sAPPalpha- regulated genes that are combinatorially regulated. by other neurotrophins are also described. It is anticipated that the results of this study may aid future development of treatments for pathological conditions dependent upon neuronal calcium deregulation.